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Paradoxical association of TET loss of function with genome-wide DNA hypomethylation

López-Moyado, Isaac F., Tsagaratou, Ageliki, Yuita, Hiroshi, Seo, Hyungseok, Delatte, Benjamin, Heinz, Sven, Benner, Christopher, Rao, Anjana·2019·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1903059116

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Abstract

Cancer genomes are characterized by focal increases in DNA methylation, co-occurring with widespread hypomethylation. Here, we show that TET loss of function results in a similar genomic footprint. Both 5hmC in wild-type (WT) genomes and DNA hypermethylation in TET -deficient genomes are largely confined to the active euchromatic compartment, consistent with the known functions of TET proteins in DNA demethylation and the known distribution of 5hmC at transcribed genes and active enhancers. In contrast, an unexpected DNA hypomethylation noted in multiple TET -deficient genomes is primarily observed in the heterochromatin compartment. In a mouse model of T cell lymphoma driven by TET deficiency ( Tet2/3 DKO T cells), genomic analysis of malignant T cells revealed DNA hypomethylation in the heterochromatic genomic compartment, as well as reactivation of repeat elements and enrichment for single-nucleotide alterations, primarily in heterochromatic regions of the genome. Moreover, hematopoietic stem/precursor cells (HSPCs) doubly deficient for Tet2 and Dnmt3a displayed greater losses of DNA methylation than HSPCs singly deficient for Tet2 or Dnmt3a alone, potentially explaining the unexpected synergy between DNMT3A and TET2 mutations in myeloid and lymphoid malignancies. Tet1 -deficient cells showed decreased localization of DNMT3A in the heterochromatin compartment compared with WT cells, pointing to a functional interaction between TET and DNMT proteins and providing a potential explanation for the hypomethylation observed in TET -deficient genomes. Our data suggest that TET loss of function may at least partially underlie the characteristic pattern of global hypomethylation coupled to regional hypermethylation observed in diverse cancer genomes, and highlight the potential contribution of heterochromatin hypomethylation to oncogenesis.

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Age-related clonal hematopoiesis associated with adverse outcomes
Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., Lindsley, R. C., Mermel, C. H., Burtt, N., Chavez, A., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408617 · Cited by 4,841
Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine
Ito, S., Shen, L., Dai, Q., Wu, S. C., Collins, L. B., Swenberg, J. A., He, C., & Zhang, Y. (2011) · Science · doi:10.1126/science.1210597 · Cited by 3,451
Mutation in TET2 in Myeloid Cancers
Delhommeau, F., Dupont, S., Valle, V. D., James, C., Trannoy, S., Massé, A., Kosmider, O., Le Couedic, J.-P., Robert, F., Alberdi, A., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810069 · Cited by 1,776
Induction of tumors in mice by genomic hypomethylation
Gaudet, F., Hodgson, J. G., Eden, A., Jackson-Grusby, L., Dausman, J., Gray, J. W., Leonhardt, H., & Jaenisch, R. (2003) · Science · doi:10.1126/science.1083558 · Cited by 1,499 · cited 6×
“Based on their overlap with nuclear lamina-associated, latereplicating domains, cancer-associated PMDs occur in the heterochromatic compartment (20, 21); their presence has been attributed to ineffective DNMT1-mediated remethylation of late-replicating genomic regions in rapidly proliferating cells (22).”
BackgroundInfluential
Multiscale 3D Genome Rewiring during Mouse Neural Development
Bonev, B., Mendelson Cohen, N., Szabo, Q., Fritsch, L., Papadopoulos, G. L., Lubling, Y., Xu, X., Lv, X., Hugnot, J.-P., Tanay, A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.043 · Cited by 1,338 · cited 1×
“Drawing on publicly available Hi-C (29), replication timing (19), and Lamina B and H3K9me2 chromatin immunoprecipitationsequencing (ChIP-seq) data (30) on mESCs, we found that regions that lost DNA methylation in all Tet-mutant mESCs (Fig.”
Method
Insulator dysfunction and oncogene activation in IDH mutant gliomas
Flavahan, W. A., Drier, Y., Liau, B. B., Gillespie, S. M., Venteicher, A. S., Stemmer-Rachamimov, A. O., Suvà, M. L., & Bernstein, B. E. (2016) · Nature · doi:10.1038/nature16490 · Cited by 1,288
Impact of cytosine methylation on DNA binding specificities of human transcription factors
Yin, Y., Morgunova, E., Jolma, A., Kaasinen, E., Sahu, B., Khund-Sayeed, S., Das, P. K., Kivioja, T., Dave, K., Zhong, F., et al. (2017) · Science · doi:10.1126/science.aaj2239 · Cited by 1,257
Transcription of IAP endogenous retroviruses is constrained by cytosine methylation
Walsh, C. P., Chaillet, J. R., & Bestor, T. H. (1998) · Nature Genetics · doi:10.1038/2413 · Cited by 1,105
TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity
Williams, K., Christensen, J., Pedersen, M. T., Johansen, J. V., Cloos, P. A. C., Rappsilber, J., & Helin, K. (2011) · Nature · doi:10.1038/nature10066 · Cited by 1,021
Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation
Baubec, T., Colombo, D. F., Wirbelauer, C., Schmidt, J., Burger, L., Krebs, A. R., Akalin, A., & Schübeler, D. (2015) · Nature · doi:10.1038/nature14176 · Cited by 705
Chromatin organization is a major influence on regional mutation rates in human cancer cells
Schuster-Böckler, B., & Lehner, B. (2012) · Nature · doi:10.1038/nature11273 · Cited by 657 · cited 3×
“Thus, most SNVs observed in Tet2/3 DKO NKT cells after transfer and expansion arise through a stochastic process occurring primarily in the heterochromatic compartment, as also observed for 16936 | www.pnas.org/cgi/doi/10.1073/pnas.1903059116 López-Moyado et al. H3K9me3-marked heterochromatic genome regions in human c…”
BackgroundInfluential
Tumour hypoxia causes DNA hypermethylation by reducing TET activity
Thienpont, B., Steinbacher, J., Zhao, H., D’Anna, F., Kuchnio, A., Ploumakis, A., Ghesquière, B., Van Dyck, L., Boeckx, B., Schoonjans, L., et al. (2016) · Nature · doi:10.1038/nature19081 · Cited by 635 · cited 1×
“More recently, however, TET loss of function in solid cancers has been increasingly attributed to hypoxia (59), or to a variety of metabolic alterations that decrease α-ketoglutarate levels or increase the levels of 2-hydroxyglutarate (10, 11).”
Background
Heterochromatin: Guardian of the Genome
Janssen, A., Colmenares, S. U., & Karpen, G. H. (2018) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100617-062653 · Cited by 500
DNA methylation loss in late-replicating domains is linked to mitotic cell division
Zhou, W., Dinh, H. Q., Ramjan, Z., Weisenberger, D. J., Nicolet, C. M., Shen, H., Laird, P. W., & Berman, B. P. (2018) · Nature Genetics · doi:10.1038/s41588-018-0073-4 · Cited by 405 · cited 3×
“PMDs have also been documented in CD4 T cells from a 103-y-old individual compared with those from a newborn human (22), suggesting that DNA methylation is also progressively lost in the heterochromatin of cells undergoing sustained longterm proliferation.”
Background
Global changes in the nuclear positioning of genes and intra- and interdomain genomic interactions that orchestrate B cell fate
Lin, Y. C., Benner, C., Mansson, R., Heinz, S., Miyazaki, K., Miyazaki, M., Chandra, V., Bossen, C., Glass, C. K., & Murre, C. (2012) · Nature Immunology · doi:10.1038/ni.2432 · Cited by 281
Transformation of Accessible Chromatin and 3D Nucleome Underlies Lineage Commitment of Early T Cells
Hu, G., Cui, K., Fang, D., Hirose, S., Wang, X., Wangsa, D., Jin, W., Ried, T., Liu, P., Zhu, J., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.01.013 · Cited by 199
Tet2 and Tet3 cooperate with B-lineage transcription factors to regulate DNA modification and chromatin accessibility
Lio, C.-W., Zhang, J., González-Avalos, E., Hogan, P. G., Chang, X., & Rao, A. (2016) · eLife · doi:10.7554/elife.18290 · Cited by 170
Self-citation

Research works printed but not linked: 43

M. Tahiliani ., Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009). · DOI · Paper page
Y. F. He ., Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011). · DOI
X. Wu, Y. Zhang, TET-mediated active DNA demethylation: Mechanism, function and beyond. Nat. Rev. Genet. 18, 517–534 (2017). · DOI · Paper page
M. Ko ., Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468, 839–843 (2010). · DOI · Paper page
S. M. Langemeijer ., Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat. Genet. 41, 838–842 (2009). · DOI · Paper page
F. Lemonnier ., Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood 120, 1466–1469 (2012). · DOI · Paper page
L. Cimmino ., TET1 is a tumor suppressor of hematopoietic malignancy. Nat. Immunol. 16, 653–662 (2015). · DOI
M. Ko, J. An, A. Rao, DNA methylation and hydroxymethylation in hematologic differentiation and transformation. Curr. Opin. Cell Biol. 37, 91–101 (2015). · DOI
S. Raffel ., BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature 551, 384–388 (2017). · DOI · Paper page
G. C. Hon ., 5mC oxidation by Tet2 modulates enhancer activity and timing of transcriptome reprogramming during differentiation. Mol. Cell 56, 286–297 (2014). · DOI · Paper page
A. Tsagaratou ., TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells. Nat. Immunol. 18, 45–53 (2017). · DOI · Paper page
F. Lu, Y. Liu, L. Jiang, S. Yamaguchi, Y. Zhang, Role of Tet proteins in enhancer activity and telomere elongation. Genes Dev. 28, 2103–2119 (2014). · DOI
J. An ., Acute loss of TET function results in aggressive myeloid cancer in mice. Nat. Commun. 6, 10071 (2015). · DOI
E. Lieberman-Aiden ., Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009). · DOI · Paper page
B. van Steensel, A. S. Belmont, Lamina-associated domains: Links with chromosome architecture, heterochromatin, and gene repression. Cell 169, 780–791 (2017). · DOI · Paper page
I. Hiratani ., Global reorganization of replication domains during embryonic stem cell differentiation. PLoS Biol. 6, e245 (2008). · DOI
B. P. Berman ., Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat. Genet. 44, 40–46 (2011). · DOI · Paper page
G. C. Hon ., Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. Genome Res. 22, 246–258 (2012). · DOI · Paper page
S. B. Baylin, P. A. Jones, Epigenetic determinants of cancer. Cold Spring Harb. Perspect. Biol. 8, a019505 (2016). · DOI · Paper page
X. Zhang ., DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells. Nat. Genet. 48, 1014–1023 (2016). · DOI · Paper page
Y. Huang ., The behaviour of 5-hydroxymethylcytosine in bisulfite sequencing. PLoS One 5, e8888 (2010). · DOI
A. Poleshko ., Genome-nuclear lamina interactions regulate cardiac stem cell lineage restriction. Cell 171, 573–587.e14 (2017). · DOI
Y. Huang ., Distinct roles of the methylcytosine oxidases Tet1 and Tet2 in mouse embryonic stem cells. Proc. Natl. Acad. Sci. U.S.A. 111, 1361–1366 (2014). · DOI
A. Bendelac, P. B. Savage, L. Teyton, The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2007). · DOI
R. Z. Chen, U. Pettersson, C. Beard, L. Jackson-Grusby, R. Jaenisch, DNA hypomethylation leads to elevated mutation rates. Nature 395, 89–93 (1998). · DOI
A. Eden, F. Gaudet, A. Waghmare, R. Jaenisch, Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300, 455 (2003). · DOI
L. B. Alexandrov .; Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain, Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013). Erratum in: Nature 502, 258 (2013). · DOI · Paper page
P. Zeller ., Histone H3K9 methylation is dispensable for Caenorhabditis elegans development but suppresses RNA:DNA hybrid-associated repeat instability. Nat. Genet. 48, 1385–1395 (2016). · DOI · Paper page
Q. Zhu ., Heterochromatin-encoded satellite RNAs induce breast cancer. Mol. Cell 70, 842–853.e7 (2018). · DOI
M. P. Crossley, M. Bocek, K. A. Cimprich, R-loops as cellular regulators and genomic threats. Mol. Cell 73, 398–411 (2019). · DOI
S. J. Boguslawski ., Characterization of monoclonal antibody to DNA.RNA and its application to immunodetection of hybrids. J. Immunol. Methods 89, 123–130 (1986). · DOI
L. Couronné, C. Bastard, O. A. Bernard, TET2 and DNMT3A mutations in human T-cell lymphoma. N. Engl. J. Med. 366, 95–96 (2012). · DOI · Paper page
O. Odejide ., A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood 123, 1293–1296 (2014). · DOI · Paper page
M. Jeong ., Large conserved domains of low DNA methylation maintained by Dnmt3a. Nat. Genet. 46, 17–23 (2014). · DOI · Paper page
R. Lister ., Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471, 68–73 (2011). · DOI
X. Li ., Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling. Proc. Natl. Acad. Sci. U.S.A. 113, E8267–E8276 (2016).
H. A. Cruickshanks ., Senescent cells harbour features of the cancer epigenome. Nat. Cell Biol. 15, 1495–1506 (2013). · DOI · Paper page
K. E. Bachman, M. R. Rountree, S. B. Baylin, Dnmt3a and Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin. J. Biol. Chem. 276, 32282–32287 (2001). · DOI
M. Manzo ., Isoform-specific localization of DNMT3A regulates DNA methylation fidelity at bivalent CpG islands. EMBO J. 36, 3421–3434 (2017). · DOI
T. Gu ., DNMT3A and TET1 cooperate to regulate promoter epigenetic landscapes in mouse embryonic stem cells. Genome Biol. 19, 88 (2018). · DOI
L. M. Iyer ., Lineage-specific expansions of TET/JBP genes and a new class of DNA transposons shape fungal genomic and epigenetic landscapes. Proc. Natl. Acad. Sci. U.S.A. 111, 1676–1683 (2014). · DOI
G. L. Xu ., Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402, 187–191 (1999). · DOI
T. Mazor, A. Pankov, J. S. Song, J. F. Costello, Intratumoral heterogeneity of the epigenome. Cancer Cell 29, 440–451 (2016). · DOI

Clonal hematopoiesis: Mutation-specific adaptation to environmental change
Florez, M. A., Tran, B. T., Wathan, T. K., DeGregori, J., Pietras, E. M., & King, K. Y. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.05.006 · Cited by 129
RNA m5C oxidation by TET2 regulates chromatin state and leukaemogenesis
Zou, Z., Dou, X., Li, Y., Zhang, Z., Wang, J., Gao, B., Xiao, Y., Wang, Y., Zhao, L., Sun, C., et al. (2024) · Nature · doi:10.1038/s41586-024-07969-x · Cited by 103

See all 131

Authors: López-Moyado, I. F., Tsagaratou, A., Yuita, H., Seo, H., Delatte, B., Heinz, S., Benner, C., & Rao, A.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2019-08
Volume: 116
Issue: 34
Pages: 16933-16942
ISSN: 0027-8424
1091-6490
DOI: 10.1073/pnas.1903059116
Cited by: 131
References: 17
Language: en
Licence: www.pnas.org/site/aboutpnas/licenses.xhtml (vor, 184 d)

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Paradoxical association of TET loss of function with genome-wide DNA hypomethylation

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